rs8589

Positions:

• chr6-49435569-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000255.4(MMUT):​c.2011A>G​(p.Ile671Val) variant causes a missense change. The variant allele was found at a frequency of 0.606 in 1,613,526 control chromosomes in the GnomAD database, including 300,357 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (26674 hom., cov: 33)
  • Exomes 𝑓: 0.61 (273683 hom.)
• Consequence: MMUT NM_000255.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 3.90

Genes affected

MMUT (HGNC:7526): (methylmalonyl-CoA mutase) This gene encodes the mitochondrial enzyme methylmalonyl Coenzyme A mutase. In humans, the product of this gene is a vitamin B12-dependent enzyme which catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA, while in other species this enzyme may have different functions. Mutations in this gene may lead to various types of methylmalonic aciduria. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a domain B12-binding (size 132) in uniprot entity MUTA_HUMAN there are 17 pathogenic changes around while only 1 benign (94%) in NM_000255.4
• BP4: Computational evidence support a benign effect (MetaRNN=7.249867E-5).
• BP6: Variant 6-49435569-T-C is Benign according to our data. Variant chr6-49435569-T-C is described in ClinVar as [Benign]. Clinvar id is 92685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-49435569-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.631 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMUT	NM_000255.4	c.2011A>G	p.Ile671Val	missense_variant	12/13	ENST00000274813.4	NP_000246.2
MMUT	XM_005249143.4	c.2011A>G	p.Ile671Val	missense_variant	12/13		XP_005249200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMUT	ENST00000274813.4	c.2011A>G	p.Ile671Val	missense_variant	12/13	1	NM_000255.4	ENSP00000274813	P1

Frequencies

GnomAD3 genomes AF: 0.588 AC: 89383 AN: 151988 Hom.: 26651 Cov.: 33

Gnomad AFR AF: 0.592

Gnomad AMI AF: 0.638

Gnomad AMR AF: 0.436

Gnomad ASJ AF: 0.564

Gnomad EAS AF: 0.460

Gnomad SAS AF: 0.650

Gnomad FIN AF: 0.602

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.625

Gnomad OTH AF: 0.554

GnomAD3 exomes AF: 0.562 AC: 140906 AN: 250646 Hom.: 41159 AF XY: 0.573 AC XY: 77571 AN XY: 135460

Gnomad AFR exome AF: 0.595

Gnomad AMR exome AF: 0.316

Gnomad ASJ exome AF: 0.546

Gnomad EAS exome AF: 0.468

Gnomad SAS exome AF: 0.647

Gnomad FIN exome AF: 0.593

Gnomad NFE exome AF: 0.621

Gnomad OTH exome AF: 0.556

GnomAD4 exome AF: 0.608 AC: 888933 AN: 1461420 Hom.: 273683 Cov.: 55 AF XY: 0.610 AC XY: 443448 AN XY: 726986

Gnomad4 AFR exome AF: 0.586

Gnomad4 AMR exome AF: 0.331

Gnomad4 ASJ exome AF: 0.550

Gnomad4 EAS exome AF: 0.439

Gnomad4 SAS exome AF: 0.641

Gnomad4 FIN exome AF: 0.599

Gnomad4 NFE exome AF: 0.626

Gnomad4 OTH exome AF: 0.595

GnomAD4 genome AF: 0.588 AC: 89445 AN: 152106 Hom.: 26674 Cov.: 33 AF XY: 0.583 AC XY: 43327 AN XY: 74362

Gnomad4 AFR AF: 0.592

Gnomad4 AMR AF: 0.435

Gnomad4 ASJ AF: 0.564

Gnomad4 EAS AF: 0.460

Gnomad4 SAS AF: 0.650

Gnomad4 FIN AF: 0.602

Gnomad4 NFE AF: 0.625

Gnomad4 OTH AF: 0.553

Alfa AF: 0.604 Hom.: 51194

Bravo AF: 0.568

TwinsUK AF: 0.636 AC: 2360

ALSPAC AF: 0.626 AC: 2411

ESP6500AA AF: 0.588 AC: 2590

ESP6500EA AF: 0.617 AC: 5304

ExAC AF: 0.574 AC: 69652

Asia WGS AF: 0.547 AC: 1906 AN: 3478

EpiCase AF: 0.606

EpiControl AF: 0.600

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Benign:6

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jan 03, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 28, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 58% of total chromosomes in ExAC -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	6.8
DANN	Benign	0.39
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.000072	T
MetaSVM	Benign	-0.72	T
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.72	N
REVEL	Uncertain	0.31
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.044
MPC		0.076
ClinPred		0.0037	T
GERP RS		4.9
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs8589; hg19: chr6-49403282; COSMIC: COSV51274081;